Responder analysis to demonstrate the effect of targeting type 2 inflammatory mechanisms with dupilumab across objective and patient‐reported endpoints for patients with severe chronic rhinosinusitis with nasal polyps in the SINUS‐24 and SINUS‐52 studies

Abstract

The involvement of multiple disease domains in CRSwNP requires assessment of a variety of clinical endpoints, however, analyses of within-patient response across different dimensions of CRSwNP are lacking. We assessed the within-patient treatment effect of dupilumab using responder definitions that combine objective (NPS) and patient-reported endpoints. Dupilumab-treated patients were significantly more likely to achieve response versus placebo from the earliest timepoints measured and at all subsequent timepoints, across different composite responder definitions. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2-mediated inflammatory disease of the paranasal sinuses associated with a high disease burden and poor health-related quality of life.1, 2 The symptoms of CRSwNP most important to patients include nasal congestion/obstruction (NC), loss of smell (LoS) and anterior/posterior rhinorrhoea.1, 3, 4 Many patients with CRSwNP have comorbid conditions associated with type 2 inflammation, such as asthma and nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD), which can add to the disease burden. Standard-of-care treatment with intranasal corticosteroids (INCS), systemic corticosteroids (SCS) or sinonasal surgery frequently fails to provide adequate symptom relief,3 and patients experience high rates of nasal polyp recurrence and incomplete smell recovery following surgery.5 Dupilumab is a fully human VelocImmune®-derived monoclonal antibody that binds to interleukin (IL)-4Rα to block the shared receptor component for IL-4 and IL-13—key and central drivers of type 2 inflammation in multiple diseases.6, 7 In the randomized phase 3 studies SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454), dupilumab added to INCS significantly improved objective outcomes and symptoms in patients with severe CRSwNP versus placebo and was well tolerated.5 Therapy continuation decisions rely on recognition of treatment response.8 Evidence indicates that objective measures and patient-reported outcomes (PROs) are often not correlated in CRSwNP, which necessitates a multifactorial assessment of disease control in clinical practice.9 While results for multiple endpoints are commonly reported in trials in CRSwNP, analyses of within-patient response across different dimensions of CRSwNP are lacking. Consequently, it may not be reported whether, and to what extent, individual patients achieve improvement in more than 1 dimension of the disease. To begin to address this knowledge gap, we investigated within-patient effects of dupilumab using responder definitions that combine objective and patient-reported endpoints. We assessed patients with severe CRSwNP enrolled in SINUS-24/SINUS-52, including subgroups of patients with asthma/NSAID-ERD, evaluating composite and pragmatic clinical endpoints of patient response versus placebo from baseline to weeks 24 and 52 of the studies. Details of the SINUS-24/SINUS-52 studies have been published.5 Patients were randomized 1:1 to subcutaneous (SC) dupilumab 300 mg or placebo (n = 143/133) every 2 weeks (q2w) for 24 weeks (SINUS-24), or 1:1:1 to dupilumab 300 mg SC or placebo q2w for 52 weeks (n = 150/153), or dupilumab 300 mg SC q2w for 24 weeks, then every 4 weeks for 28 weeks (n = 145) (SINUS-52). Patients provided written informed consent. The objective endpoint was bilateral nasal polyp score (NPS; range 0–8). PRO symptom scores were NC/LoS/rhinorrhoea (anterior/posterior) (all ranged 0–3; hereafter termed symptom scores). Higher scores indicate greater disease burden. Outcomes were compared between patients with dupilumab 300 mg q2w and placebo from baseline to week 24 (SINUS-24) or 52 (SINUS-52). Analyses were conducted in the intent-to-treat population and patients with comorbid asthma, NSAID-ERD, prior surgery, SCS use within the previous 2 years or double-standard-dosage mometasone furoate nasal spray (400 μg) during the treatment period. Responder analyses evaluated the proportion of patients with baseline NPS and symptom scores ≥1 or ≥2, who achieved ≥1- or ≥2-point improvement in NPS or any symptom score, or ≥1- or ≥2-point improvement in NPS and any symptom score. Odds ratios (ORs) and 95% confidence intervals (CIs) derived from the Mantel-Haenszel estimator. p-values determined with the Cochran-Mantel-Haenszel test on the association between responder status and treatment group (dupilumab versus placebo), stratified by asthma/NSAID-ERD status, prior surgery history and region. Patients indicated for surgery for CRSwNP or SCS for any reason were considered as non-responders for timepoints after surgery or SCS use. Patients with missing data at the visit of interest were also considered as non-responders. Patient baseline characteristics in the intention to treat population were balanced across the treatment groups and were consistent with severe CRSwNP with respect to symptom burden, surgeries, corticosteroid use and disease comorbidities.5 Across all responder definitions, significantly more patients achieved response with dupilumab than with placebo from the first NPS assessment onward (Figure 1). By week 24 in SINUS-24, 91% of dupilumab-treated patients achieved ≥1-point improvement in NPS or any symptom score, and 61% achieved ≥1-point improvement in NPS and any symptom score, compared with 43% and 13%, respectively, in the placebo group (ORs 14.0 and 10.8; both p < .0001; Figure 1A,B). At weeks 24/52 in SINUS-52, 81%/79% of dupilumab-treated patients, respectively, achieved ≥1-point improvement in NPS or any symptom score, compared with 37%/31% with placebo (ORs 7.3 and 8.9; both p < .0001; Figure 1C). The corresponding values for NPS and any symptom score were 53%/65% at weeks 24/52 respectively, with dupilumab, compared with 6%/10% with placebo (ORs 18.8 and 24.8; both p < .0001; Figure 1D). When the more stringent responder definition of ≥2-point improvement was used, at week 52 in SINUS-52, 68% of patients achieved ≥2-point improvement in NPS or any symptom score, and 43% achieved ≥2-point improvement in NPS and any symptom score, compared with 16% and 3%, respectively, in the placebo group (ORs 14.3 and 23.6; both p < .0001; Figure 1E,F). Notably, responder rates with dupilumab were generally sustained throughout the studies, and in the case of the NPS and symptom improvement definition (Figure 1), responder rates increased progressively throughout the studies, without an apparent plateau of treatment effect. In contrast, responder rates with placebo, as well as being significantly lower than with dupilumab at all timepoints, showed no progressive increase. Figure S1 shows percentage change from baseline to weeks 24 and 52 across all endpoints assessed in this analysis. The area enclosed by the dupilumab curves completely surrounds the area enclosed by the placebo curves, indicating that percentage change was greater with dupilumab versus placebo at weeks 24 and 52 in SINUS-24 and SINUS-52, respectively, across all endpoints, with up to 58% mean reduction in NC and >50% reduction in LoS score and anterior/posterior rhinorrhoea in both studies (Figure S1). Of patients who achieved ≥1-point improvements with placebo, more achieved improvements in patient-reported symptom scores than NPS; in contrast, similar proportions of patients achieved NPS and symptom score improvements with dupilumab (Figure 2). A significantly greater proportion of patients with CRSwNP and asthma, NSAID-ERD, prior surgery, SCS use within 2 years or double-standard-dosage INCS responded to treatment with dupilumab versus placebo at weeks 24/52 (Figure S2). The involvement of multiple disease domains in CRSwNP requires assessment of a variety of clinical endpoints. Dupilumab has previously demonstrated improvements versus placebo in NPS and individual symptoms of severe CRSwNP.5 However, composite clinical endpoints, which allow a comprehensive assessment of signs and symptoms of CRSwNP and its severity, are lacking. We assessed the treatment effect of dupilumab across different composite responder definitions. In the absence of established response thresholds for within-patient change, ≥1- and ≥2-point improvements in NPS/NC/LoS/rhinorrhoea (anterior/posterior) scores were used. Dupilumab-treated patients were significantly more likely to achieve response versus placebo from the earliest timepoints measured and at all subsequent timepoints, including when more stringent responder criteria were applied, such as the requirement for improvements in both objective and patient-reported measures. Few patients in the placebo groups achieved NPS improvement (Figure 2, Figure S1), and the early increase in patients achieving ≥1-point improvement in NPS or any symptom score in the placebo groups was not sustained and began to decline before the end of the study. In contrast, the rapid early increase in patients achieving ≥1-point improvement in NPS or any symptom score with dupilumab was sustained through the end of the studies. The profile for patients achieving ≥1-point improvement in NPS and any symptom score showed a different pattern: The dupilumab groups exhibited an initial rapid increase followed by a gradual, sustained improvement throughout the study period, whereas the placebo groups showed low and unsustained responder rates, likely due to few placebo-group patients achieving ≥1-point improvement in NPS. Taken together, these data suggest that patient-reported symptom scores were driving the early increase in improvement in the NPS or any symptom score threshold. The observation that responder rates were sustained in the dupilumab group but not the placebo group supports the role of improvement in NPS in maintaining and promoting reduction in symptoms. Moreover, improvement in a symptom score, without concomitant improvement in NPS, may not be clinically meaningful given this was frequently observed in the placebo group (13.2% of patients with placebo versus 2.3% with dupilumab). On the contrary, improvement in NPS with dupilumab was almost always accompanied by improvement in at least one symptom (65.1% of patients with dupilumab versus 9.5% with placebo), and most commonly by improvement in both NC/rhinorrhoea and sense of smell (Figure 2). Patients with CRSwNP with comorbid asthma, NSAID-ERD, prior surgery, SCS use within 2 years or double-standard-dosage INCS were also significantly more likely to achieve response with dupilumab versus placebo. Substantial improvements from baseline were observed in the objective outcome and PROs with dupilumab at weeks 24 and 52. These data further demonstrate the comprehensive and sustained effects of targeting the type 2 inflammatory pathway by dual IL-4/IL-13 inhibition with dupilumab on NPS, an objective measure of disease, and symptoms of severe CRSwNP. To the authors’ knowledge, composite responder analyses have not been reported for other biologics in CRSwNP. In the absence of parameters that predict response to biologics in CRSwNP, comprehensive treatment effect may offer another approach for informing treatment decisions. This analysis demonstrates that patients with CRSwNP can achieve response in both objective disease measures and PROs, despite the fact that the 2 are often not correlated.9 This dual effect may reflect the broad mechanism of action of dupilumab, targeting multiple aspects of type 2 inflammation in patients with CRSwNP.6, 7 Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov Identifiers: NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52). Medical writing/editorial assistance provided by Joseph Hodgson, PhD, of Adelphi Group, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. C. Bachert: ALK, AstraZeneca, GlaxoSmithKline, Mylan, Novartis, Sanofi, Stallergenes Greer—advisory board member and speakers’ fees. A. T. Peters: Regeneron Pharmaceuticals, Inc., Sanofi – advisory board member; AstraZeneca—research support and advisory board member; Optinose – consultant and research support. E. Heffler: AstraZeneca, Boehringer Ingelheim, Circassia, GlaxoSmithKline, Nestlè Purina, Novartis, Sanofi Genzyme, Teva, Valeas—research grants. J. K. Han: AstraZeneca, Genetech, Novartis, Sanofi Genzyme, Regeneron Pharmaceuticals, Inc. H. Olze: Sanofi—advisory board member and speakers’ fees; Novartis—speakers’ fees. O. Pfaar: ALK-Abelló, Allergopharma, Anergis S.A., ASIT Biotech Tools SA, Bencard Allergie GmbH/Allergy Therapeutics, GlaxoSmithKline, HAL Allergy Holding BV/HAL Allergie GmbH, Laboratorios LETI/LETI Pharma, Lofarma, Stallergenes Greer—research grants and personal fees; Biomay, Circassia, Immunotek S.L., Pohl-Boskamp—research grants; Astellas Pharma Global, EUFOREA, Indoor Biotechnologies, Ingress-Health HWM, John Wiley and Sons AS, Med Update Europe GmbH, MEDA Pharma/MYLAN, Mobile Chamber Experts (a GA2LEN Partner), Novartis, Paul-Martini-Stiftung, Regeneron Pharmaceuticals, Inc., Roxall Medizin, Sanofi-Aventis, Sanofi-Genzyme, streamedup! GmbH—personal fees. C.-C. Chuang, R. Rout, L. Goga, J.A. Jacob-Nara and P.J. Rowe: Sanofi—employees, may hold stock and/or stock options in the company. R. Attre, Y. Deniz, Z. Chen, S. Kamat and S. Siddiqui: Regeneron Pharmaceuticals, Inc.—employees and shareholders. All authors provided critical review and revision and final approval of the publication and accept accountability for the accuracy and integrity of the content. CB and ATP contributed to the study concept or design, acquired data, and provided interpretation/analysis of the data. EH, HO and OP provided data interpretation/analysis. JKH acquired data and provided data interpretation/analysis. C-CC, RR, RA, LG, JAJ-N, PR, YD, ZC, SK and SS contributed to the study concept or design and provided data interpretation/analysis. The local institutional review board or ethics committee at each study centre oversaw trial conduct and documentation. All patients provided written informed consent before participating in the trial. Qualified researchers may request access to patient-level data and related study documents including clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data-sharing criteria, eligible studies and process for requesting access can be found at https://www.clinicalstudydatarequest.com. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.